Our prior research suggests that serotonergic systems area involved in the pathophyisology of seasonal affective disorder (SAD) and the mechanism of action of light therapy. The 5HT-2C serotonin agonist m-CPP has produced exaggerated activation and euphoria in untreated SAD patients (PTS) in winter; and abnormal hormonal responses have ocurred in response to m-CPP and to the 5HT-1A agonist ipsapirone. This year we followed-up these studies by: a) analyzing growth hormone (GH) and norepinephrine (NE) responses to m-CPP, and relating induced core body temperature responses to overnight temperature profiles and hormonal measures; b) analyzing the effects of the serotonin antagonist metergoline; and, c) analyzing serotonin-related candidate genes. PTS and healthy controls (CRTS) were previoulsy given infusions of m-CPP or placebo in light-treated and -untreated condtions. Because of data from our lab indicating that 1) sympathetic nervous system responsiveness may be impaired in SAD, and 2) nocturnal temperature regulation may play a role in the pathophysiology of SAD, we evaluated both m-CPP-induced plasma NE concentrations, and the relationship between neuroendocrine profiles and nocturnal temperature profiles. Core body temperature elevations seen after m-CPP infusion did not differ between groups. In both PTS and CRTS, these elevations appeared to be due to increased metabolic thermogenesis. Core body temperature elevations were proportional to the previous nights' core temperature minima in both PTS and CRTS; a relationship that did not differ across groups or light treatment conditions. PTS had blunted NE responses compared with CRTS. Finally, light treatment lowered GH concentrations over time in PTS, but raised them in CRTS. In a second study, 16 PTS were given a single dose of metergoline or placebo, one week apart, under both untreated and light treated conditions. Mood was rated both subjectively and via SIGH-SAD and HIGH- SAD clinical ratings. PTS kept prospective logs of their hours of sleep, and activity was monitored via activity monitors. An antidepressant effect following a single dose of metergoline, as measured by the SIGH- SAD atypical depressive symptoms in the untreated condition; an effect that took several days to reach its full magnitude. Similar trends were seen for typical depressive symptoms in the untreated condition and for both types of symptoms in the light-treated condition. The following serotonin-related genes have been studied in 51 PTS and 47 CRTS: 5-HT1A, 5-HT1Da and b, 5-HT1E, 5-HT2A, 5-HT2C and 5-HT7. To date, we have found no differences between PTS and CRTS in these genes. However, the following non-synonymous genetic variants in the form of amino-acid substituions were found in both groups: 1) Ala to Val and His to Tyr in the 5HT-2A receptior, and 2) Cis to Ser in the 5HT-2C receptor. Platelets in PTS with mutation showed prolonged Ca2+ response after 5-HT stimulation.